Current advances on the therapeutic potential of scutellarin: an updated review

Scutellarin is widely distributed in Scutellaria baicalensis, family Labiatae, and Calendula officinalis, family Asteraceae, and belongs to flavonoids. Scutellarin has a wide range of pharmacological activities, it is widely used in the treatment of cerebral infarction, angina pectoris, cerebral thrombosis, coronary heart disease, and other diseases. It is a natural product with great research and development prospects. In recent years, with in-depth research, researchers have found that wild scutellarin also has good therapeutic effects in anti-tumor, anti-inflammatory, anti-oxidation, anti-virus, treatment of metabolic diseases, and protection of kidney. The cancer treatment involves glioma, breast cancer, lung cancer, renal cancer, colon cancer, and so on. In this paper, the sources, pharmacological effects, in vivo and in vitro models of scutellarin were summarized in recent years, and the current research status and future direction of scutellarin were analyzed. Graphical Abstract

Toxicological studies have proved that scutellarin is a slightly toxic or non-toxic natural small-molecule flavone compound, and the safe dose of LD50 value is 10 g/kg [17].Based on the advantages of low toxicity and a wide range of sources, researchers found that scutellarin has a variety of pharmacological activities, including cardiovascular [18] and cerebrovascular diseases [19,20], treatment of a variety of cancer therapies [21], and antiinflammatory effects.In recent years, scutellarin played an important role in the treatment and protective effects of liver and kidney function caused by diabetes, the damage of brain, heart, liver, and kidney organs caused by alcohol, and eye diseases.
Animal models and cell models are important pharmacological research methods to evaluate drug activity and explore drug mechanisms, which usually need to be comprehensively evaluated by in vitro and in vivo methods combined with various models.Based on the study of different pharmacological activities of scutellarin in recent years, we combined the mechanism of scutellarin with in vivo and in vitro models to update the research progress of scutellarin's pharmacological effects and look for changes and breakthroughs in recent years.

Anti-cerebrovascular disease effect
Scutellarin is widely used in the clinical treatment of cerebral ischemia because of its anti-inflammatory, antioxidant, and vasodilator effects.The key feature of cerebral ischemia is that microglia in the brain evolve from a quiescent, branching morphology to an activated, unbranched, amoeboid morphology, which releases a large number of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), inter-leukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and other inflammatory mediators.TNF-α, IL-1β, iNOS, and reactive oxygen species (ROS), thereby exacerbating local inflammation and neuronal damage [22].Chen et al. [23] found that scutellarin inhibited phosphorylated c-Jun N-terminal kinase (p-JNK), peripheral blood phosphorylated p38 mitogen-activated protein kinase (p-p38), and down-regulated inflammation in microglia by modulating the mitogen-activated protein kinases (MAPKs) pathway through the establishment of a permanent cerebral arterial occlusion model (MCAO).In addition, it can also significantly upregulate the expression level of extracellular  Thymus mongolicus (Ronniger) Ronn.+ Dried whole herb and above-ground part 80% Ethanol [12] Perilla frutescens (L.) Britt.+ Roots, stems, leaves and fruits 80% Ethanol [13] Rosmarinus officinalis + Dried whole herb 65% Ethanol [14] Juniperus rigida S.et Z. + Branches and cones 70% Ethanol [15] Patrinia villosa + Dried whole herb 60% Ethanol [16] signal-regulated kinase1/2 (p-ERK1/2), which can play a neuroprotective role.NIU [24] and others simulated neonatal hypoxic-ischemic disease (HIE) by culturing primary rat cerebral cortical neurons under the condition of hypoxia and glucose deficiency.After administration of scutellarin, it was found that scutellarin could inhibit neuronal death and regulate the Growth-associated protein (GAP43)-dependent pathway to promote axonal elongation of neurons, thus alleviating long-term nerve injury caused by HIE.Another study found that scutellarin can activate G-cyclase (GC) and produce cyclic guanosine monophosphate (cGMP) through endothelial-derived nitric oxide (NO), thus regulating the cGMP-dependent protein kinase (PKG) pathway [25][26][27].PKG is a powerful vascular tone regulator.Activated PKG induces phosphorylation of vasodilator-stimulated phosphoprotein (Vasp), which in turn activates downstream ion channels and triggers endothelium-dependent vasodilation [28,29].DENG et al. found that scutellarin can repair oxidative stress injury in mice models of cerebral ischemiareperfusion injury by down-regulating tMCAO-induced mRNA and protein expression of AR and NOX [30].MENG et al. found that scutellarin can treat cerebral ischemia by regulating MARK, phosphatidylinositol 3 kinase (PI3K), hypoxia-inducible factor-1 (HIF-1), and other pathways, thus exerting vasorelaxation, antiinflammatory and antioxidant effects [31].Jia et al. [32] found through network pharmacology and experimental validation that Scutellarin exerts therapeutic effects on cerebral ischemia by activating astrocyte JAK2/STAT3 signaling, which provides a solid experimental basis for its clinical application.Xie et al. [33] found that Scutellarin exhibited antioxidant, anti-inflammatory, and neuroprotective effects in cerebral ischemia/reperfusion injury (CIRI) through PI3K/Akt pathway-mediated Nrf2 activation.Zhang et al. [34] found that scutellarin inhibits the inflammatory process through nuclear factor κ-B p65 and p38 mitogen-activated protein kinase signaling pathways and protects against brain damage in ischemically injured rats.Wang et al. [35] found that scutellarin exerts an effective effect on acute-phase ischemic brain injury by modulating neurotransmitter activity and reducing the toxicity of excitatory amino acids in neurons.M2 Microglia can exert neuroprotective effects and promote tissue repair.Chen et al. [36] found that scutellarin may directly promote the polarization of M2 microglia and their expression of neurotrophic factors.The protective effect was exerted through the inhibition of JNK and p38 signaling pathways.In addition, lucigenin promotes the polarization of M2 microglia by enhancing the ERK1/2 signaling pathway.In addition, scutellarin may also alleviate acute alcoholic brain injury by stimulating the activity of antioxidant enzymes and inhibiting the expression of syndromic factors [37].Types of action and models of scutellarin in anti-cerebrovascular disease are showed in Table 2.

Anti-cardiovascular disease effect
Scutellarin has pharmacological effects such as slowing down heart rate, regulating myocardial contractility, dilating blood vessels, reducing cardiac preload and afterload, dilating coronary arteries, and increasing myocardial oxygen supply.It has been widely used in the clinical treatment of cardiovascular diseases.Li et al. [38] found that scutellarin mediates I/R-induced cardiomyocyte apoptosis and cardiac dysfunction by regulating the activation of Bcl-2/Bax/Caspase-3 signaling pathway, so as to improve treatment and improve ischemic heart Adult male SD rats BV-2 microglia 150 ± 10 g In vivo In vitro [36] Hypoxic-ischemic encephalopathy model (HIE) 20 mg/kg 0.1-100 μmol Timed pregnant female SD rat primary cortical neuronal cells -In vitro [24] Cerebral ischemia-reperfusion model (IR) 45, 90 mg/kg SD rats -In vivo [29] Transient middle cerebral artery occlusion (tMCAO) 50, 100 mg/kg Male C57BL/6N mice 20-24 g In vivo [30] Acute alcohol mice brain injury model 10, 25, 50 mg/kg BALB/c male mice 18-22 g In vivo [37] disease.Zhou et al. [39] found that scutellarin ameliorates I/R-induced cardiomyocyte apoptosis and cardiac dysfunction by activating the Bcl-2/Bax/Caspase-3 signaling pathway via the cGAS-STING signaling pathway.Wang et al. [40] found that scutellarin protects against myocardial ischemia-reperfusion injury EPK1/2-CREB regulates mitochondrial autophagy.Fu et al. [41] found that scutellarin significantly reduced lipid levels and increased antioxidant enzymes in atherosclerotic (AS) rats by inhibiting mammalian sterile20-like kinases 1 (Mst1) phosphorylation, Yes-associated protein (YAP) phosphorylation, phosphorylation of forkhead box O3A (FOXO3a), nuclear translocation of FOXO3a, and upregulation of protein kinase Bm (AKT) expression.Regulates downstream genes to inhibit vascular endothelial cell injury and apoptosis, thus exerting anti-AS effects.Scutellarin has also been used in the treatment of diabetic cardiomyopathy, where it can lower blood glucose, total cholesterol, triglyceride, and LDL levels, up-regulate HDL levels, down-regulate the levels of lactic dehydrogenase 1 (LDH1) and creatine kinase (CK), and promote mRNA and protein expression of autophagy-related factors Beclin-1 and Lc3-II, and inhibit the apoptosisrelated factors cysteine aspartic acid-specific protease (caspase), as well as the B-cell lymphocyte-associated X protein (BAX).Protein (BAX), and Cytochrome C (Cyt-C) mRNA and protein expression, thereby up-regulating autophagy-associated factors to promote autophagy signaling pathway and down-regulating apoptosis-associated factors to inhibit apoptosis signaling pathway, which improves the cardiac morphology and reduces apoptosis of cardiac myocytes and serves as a treatment for type 2 diabetic cardiomyopathy [42].Huo and others [43] found that scutellarin could improve oxidative stress, inflammation, and reduce apoptosis by modulating NRF2/KEAP/ ARE, TLR4/MYD88/NF-κB, and apoptosis pathways to treat and prevent myocardial injury complicated by type 2 diabetes mellitus.Qu et al. [44] used isolated rat hearts to study the effect of scutellarin on acute myocardial ischemia/reperfusion injury and found that scutellarin significantly increased the expression I/R (ischemia/ reperfusion)-induced decrease in PPARγ and Nrf2 protein, and decreased the I/R-induced elevation of NF-κB protein expression to achieve cardioprotection.scutellarin-scutellarin (PAE) polylactic acid-glycidylglycolic acid (PLGA) nanoparticles (NPs) made by combining scutellarin with PLGA were able to reduce CK, LDH, and AST levels in serum, decrease apoptosis, and improve cardiac function [45].Types and models of scutellarin action in anti-cardiovascular diseases are shown in Table 3.In vivo [43] Isolated Langendorff rat heart model 1, 5, and 25 µg/ml Male SD rats 250-300 g In vitro [44] rat myocardial ischemia (MI) 5 mg/kg Male SD rats 250 ± 20 g In vivo [45] Fig. 2 Categories of human cancers that can be prevented and treated by scutellarin

Antitumor effect
In vivo and in vitro studies have shown that scutellarin can be used for the prevention and treatment of a variety of human cancers, and the types of cancers are shown in Fig. 2. Types of action and models of scutellarin in antitumor effects are shown in Table 4.

Anti-colon cancer effect
Zeng et al. [46] found that scutellarin reduced the expression levels of TNF-α and TNF-1β in mouse serum, upregulated the expression of BAX, and down-regulated the expression level of Bcl-2 in mouse cancer tissues through down-regulation of the Wnt/β-Catenin signaling pathway, and then inhibited the proliferation and migration of HT-29 cancer cells, and induced cell apoptosis.Scutellarin is one of the active ingredients of Erigeron breviscapu (Dengzhanxixin in China) injection (EBI).By activating the necrotic RIPK3/MLKL classical signaling pathway, EBI greatly promoted intracellular ROS production, significantly inhibited the proliferation of three human colorectal cancer (CRC) cell lines, and effectively inhibited the migration and invasion of SW620 cells, thus exerting antitumor effects.In addition, in the SW620 xenograft mouse model, EBI significantly inhibited tumor growth and lung metastasis and effectively circumvented drug-resistant apoptosis providing a new therapeutic pathway for anticolon cancer [47].Scutellarin significantly ameliorated AOM/DSS-induced CAC in mice and induced apoptosis in CAC tissues by inhibiting NF κB (nuclear factor κB)mediated inflammation and the Hedgehog signaling axis.
In addition, scutellarin inhibited cell proliferation, migration, and colony formation, and induced apoptosis in SW480 cells by down-regulating the Hedgehog signaling pathway activity, and reduced NFκB-mediated inflammatory responses in TNF-α-stimulated IEC-6 cells [48].

Anti-renal cancer effect
Deng et al. [49] found that scutellarin enhanced the expression of phosphatase and tensin homologue (PTEN) protein, a bispecific protein phosphatase identified as a tumor suppressor in a variety of human malignant tumors, and that activated PTEN caused second messenger lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3) dephosphorylates, thereby contributing to its counteracting phosphatidylinositol-3-kinase (P13K) activity and AKT phosphorylation, inhibiting the PI3K/AKT pathway, which plays an important role in tumor cell proliferation, angiogenesis, and survival, and induces apoptosis of tumor cells, stalling their cell cycle at the G0/G1 phase, thus inhibiting the proliferation and invasion of renal cancer cells, suggesting that scutellarin has the potential to be a potential drug for the treatment of renal cancer.

Anti-lung cancer effect
TGF-β is considered a tumor suppressor due to its strong growth inhibitory activity in a wide range of cells.
The TGF-β/Smad signaling pathway plays an important role in tumor cell proliferation, differentiation, and apoptosis.However, scutellarin modulates this pathway to induce apoptosis in tumor cells, and it has been reported that scutellarin selectively reduces the survival rate of tumor cells without affecting normal cells [50][51][52][53].He and others [54] found that scutellarin could enhance 125 I-induced apoptosis and the antiproliferative effect of tumor cells through down-regulation of the AKT/mTOR pathway, which provided the possibility of its combination therapy.Sun and others [55] found that scutellarin could promote caspase-3-dependent apoptosis induced by the first-line antitumor drug cisplatin via the ERK/P53 pathway and promote cisplatin-induced cytotoxicity autophagy via the c-Met-AKT pathway, which in turn acted to reverse the unique properties of cisplatin resistance.

Anti-glioma cancer effect
Wang et al. [56] found that scutellarin was able to inhibit the growth of glioma, as well as the proliferation and migration of glioma cells.In addition, scutellarin could significantly reduce the expression of baculovirus inhibitor of apoptosis protein 5 (BIRC5), thereby reversing the inhibition of apoptosis in glioma cells and exerting its anti-glioma effect.Therefore, Scutellarin may become a new potential targeted drug for the treatment of gliomas.Du et al. [57] found that Scutellarin inhibited the proliferation of glioma cells by upregulating miR-15a expression.Scutellarin-induced apoptosis and cell cycle in the G2/M phase SF-295 cell line inhibited cell proliferation in a dose-dependent manner and inhibited the growth of gliomas through the p63 signaling pathway in a dosedependent manner, which was similar but weaker than the effect of 5-fluorouracil [58].

Anti-breast cancer effect
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high blood vessels and frequent metastasis.Scutellarin blocks the interaction between TNF-α and TNFR2, and inhibits the activation of RUNX1 and the production of G-CSF in endothelial cells associated with TNBC downstream, thus reducing the metastasis of TNBC [59].Scutellarin reduces the tendency of decreased connexin expression by regulating the TNFR2-ERK1/2-EZH2 signaling pathway, which inhibits TNF-α initiated vascular endothelial barrier disruption and thus reduces TNBC metastasis [60].

Treatment of other tumors
AKT is a serine/threonine kinase, belonging to the AGC family, which can regulate cell proliferation and survival, and scutellarin can activate this pathway, causing tumor cells to arrest with the G2 phase, which plays a role in the treatment of esophageal squamous carcinoma [61].Girdin is an actin-binding protein, that is involved in cancer invasion and angiogenesis, and is a prognostic biomarker.Girdin can participate in pancreatic cancer (PaCa) migration mediated by EGF signal, and SCU can inhibit cancer invasion by inhibiting Girdin, thus playing a role in anticancer [62].Li et al. used an aminoethyl anisamide-targeted copolymerization approach to amplify the delivery capacity of scutellarin to facilitate the in vivo application of scutellarin in hepatocellular carcinoma (HCC) immunotherapy and demonstrated that scutellarin has the potential to trigger immunogenic cell death (ICD) in hepatocellular carcinoma HCC [63] ).

Anti-diabetic effect 2.4.1 Therapeutic effect on insulin resistance
Insulin resistance (IR) is a condition in which the peripheral tissues of the body become less sensitive to insulin and is present in various metabolic disorders such as diabetes mellitus, obesity, and hypertension.IR can occur in the liver, muscle, and adipose tissues, and when the levels of insulin, free fatty acids, or glucose in them are elevated tissues produce ROS and oxidative stress, as a vicious cycle IR and oxidative stress reinforce each other and exacerbate the body damage.LUAN et al. found that scutellarin reduced insulin-dependent lipid accumulation and mRNA expression upregulated Akt phosphorylation and improved the insulin signaling pathway in HepG2 cells in vitro.Down-regulation of rapamycin-targeted protein (mTOR) phosphorylation and n-SREBP-1c protein levels in high-fat diet (HFD)-fed mice and reduction of lipid accumulation in IR and lipid metabolism disorders through mTOR-dependent pathways [64].Gao et al. found that scutellarin could activate the AMPK-αmediated insulin signaling pathway, which in turn upregulated P85α, activated the PI3K/AKT pathway, and ultimately affected the expression of the glucose transporter GLUT4, which indirectly exerted a hypoglycemic and lipid-lowering effect.in addition, scutellarin could also be a multi-targeted treatment for IR through its antioxidative stress, but the mechanism of the synergism of scutellarin's modulation of the AMPK pathway and the anti-oxidative stress in the treatment of IR is still unclear and needs to be further investigated [65].

Antidiabetic-induced retinal injury
Scutellarin has a favorable therapeutic effect on diabetes-induced endothelial cell damage and retinopathy (DR).Scutellarin reduces the expression of BCL2, BAX, and fine cYTC, and inhibits apoptosis through a mitochondria-dependent pathway to treat diabetes-induced endothelial cell damage.Scutellarin also improves the decrease in mitochondrial membrane potential with ROS overload, decreases the protein expression of superoxide dismutase (SOD), and promotes the expression of microtubule-associated protein LC3II and autophagyrelated gene ATG5.In addition, scutellarin can upregulate mitogen phagocytosis by modulating the PINK1/ Parkin signaling pathway, thereby exerting a protective effect against hyperglycemia-induced vascular endothelial cell injury [66].Vascular endothelial growth factor (VEGF) is the main cause of retinal neovascularization, vascular leakage, and is a therapeutic target for anti-angiogenesis in DR.Oral administration of scutellarin attenuates microvascular dysfunction caused by hyperglycemia and hypoxia in vitro and in vivo and inhibits vascular neovascularization, which may be related to its inhibition of VEGF and its downstream proteins, p-ERK, phosphorylated adhesion plaque kinase (p-FAK), and phosphorylated tyrosine protein kinase (p-Src) activation.It is evident that scutellarin is a VEGF inhibitor and has the potential to be a therapeutic agent for diabetic microangiopathy.Li et al. [67] found induced DR cell focussing in DM rats, particularly in retinal ganglion cells (RGCs), and found that scutellarin administration significantly inhibited cell focussing in DR and explained the molecular network mechanisms involved.

Antidiabetic-induced liver and kidney damage
Fan et al. [68] found that scutellarin may ameliorate T2DM liver injury by inhibiting hepatocyte apoptosis in vitro and in vivo.Huang et al. [69] found that scutellarin was effective in ameliorating various features of diabetic nephropathy (DN) in vivo, including proteinuria, glomerular dilatation, accumulation of tethered matrix, renal fibrosis, and podocyte injury, by modulating the TGF-β1 signaling pathway and its interaction with the Erk and Wnt/β-linker pathways.Scutellarin plays an important role in the treatment of diabetes and its complications, and types of action and models informations are showed in Table 5.

Therapeutic role in Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease associated with aging, characterized by progressive memory impairment, and cognitive and social decline.At present, there is no drug to cure this disease.As for the pathogenesis of AD, it is widely assumed that amyloid (Aβ) aggregates and is accompanied by the production of neurotoxic ROS.In addition, gene mutation, abnormal phosphorylation of tau protein, neuroinflammation, cholinergic injury, and imbalance of neurovascular lesions are also causes of AD.Scutellarin binds to Aβ-42 receptors in the brain, effectively inhibits the generation of Aβ oligomers and fibers, attenuates its induced neurotoxicity and reduces the expression of phosphorylated Tau protein, increases the expression levels of superoxide dismutase and acetylcholine, inhibits the expression levels of ROS and pro-inflammatory factors TNF-α and IL-6, and attenuates neuroinflammation.It also antagonizes Aβ-induced expression of anti-apoptotic protein Bcl2, inhibits expression of pro-apoptotic protein Bax and cleaved caspase 3, reduces apoptosis, and alleviates AD [70][71][72][73].Defective mitochondrial bioenergetics and its resulting low glucose metabolism are key pathophysiologic regulators that promote neurodegeneration, Sheng et al. [74] found that scutellarin rescue mitochondrial damage by improving mitochondrial glucose oxidation via the Pdk-Pdc axis and that active components that ameliorate mitochondrial bioenergetic deficiencies may be valuable in the treatment of neurological disorders.Microglia are essential for the development and homeostasis of the neonatal central nervous system (CNS).Types of action and models of scutellarin in the treatment of Alzheimer's diseases are showed in Table 6.

Anti-inflammatory effect
As a natural small molecule, scutellarin has good antiinflammatory activity and can be used in the prevention and treatment of pneumonia, arthritis, and neuroinflammation.scutellarin can inhibit the inflammatory response by modulating the NF-ĸb/NLRP3 pathway, which exerts an antagonistic effect [75].Lipopolysaccharide (LPS) is a common inflammatory factor that activates the inflammatory sensory protein caspase-11 and produces an inflammatory response.Scutellarin induces Ser/Thr phosphorylation of caspase-11 at PKA-specific sites, which counteracts the activation of caspase11 and antagonizes the inflammatory response caused by LPS [76].Cerebrovascular diseases are often accompanied by neuroinflammation, which can lead to increased morbidity and mortality.In the central nervous system, microglia are resident innate immune cells Neuroinflammation is regulated by microglia, which play a dual role in the developing brain, both neuroprotective and neurotoxic.Activated microglia release inflammatory factors such as TNF-α, IL-1β, and NO, which further stimulate microglia activation and promote the accumulation of pro-inflammatory mediators, ultimately leading to neuronal death and exacerbating brain damage.Scutellarin can inhibit the production of inflammatory factors by regulating the AKT/NF-κB and p38/JNK pathways, which in turn inhibits microglia activation to alleviate neuroinflammation [77].In addition, it has been shown that scutellarin can also alleviate and treat osteoarthritis by modulating the NF-ĸB pathway [78].Yang et al. [79] found that scutellarin significantly reduced subchondral bone loss and cartilage degeneration in a mouse model of cartilage injury in medial meniscus (DMM) destabilization and in ovariectomy (OVX)-induced mouse subchondral bone loss.By inhibiting interleukin 1β-induced extracellular matrix degradation of cartilage NF-κB/mitogen-activated protein kinase (NF-κB/MAPK) signaling pathway.Li et al. [80] found that scutellarin attenuated complete Freund's adjuvant (CFA)-induced rheumatoid arthritis (RA) in mice by modulating the Keap1/Nrf2/HO-1 pathway, and the results provide preliminary evidence for the treatment of arthritis with Scutellarin.Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology that lacks effective treatments, Aksit et al. [81] found that scutellarin may prevent UC by downregulating proinflammatory cytokines and inhibiting apoptosis and oxidative stress.Types of action and models of scutellarin in anti-inflammatory effects are shown in Table 7.

Antioxidant effect
The presence of phenolic hydroxyl groups in the chemical structure of scutellarin provides hydrogen atoms to exert antioxidant effects.Scutellarin can effectively scavenge a variety of free radicals such as  [83].
Types of action and models of scutellarin in antioxidan effect is shown in Table 7.

Antiviral effect
Modern studies have shown that scutellarin has some antiviral activity.Its antiviral pharmacological action is a specific manifestation of the purgative and detoxifying action in classical Chinese medicine [84].Details of scutellarin's antiviral activity were reported as research progressed.
Wang et al. [85] found that scutellarin significantly inhibited the activities of sortase A (SrtA) and caseinolytic peptidase P (ClpP) of methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 by screening hundreds of compounds, fluorescence quenching assay and molecular docking results showed that scutellarin directly binds to SrtA molecules, and also inhibits hemolytic activity of Staphylococcus aureus (SA) by inhibiting Hla expression in a SrtA-independent way.It can also inhibit the hemolytic activity of SrtA by suppressing the expression of Hla in a SrtA-independent manner.Therefore, the combination of scutellarin with vancomycin has the effect of preventing MRSA invasion of A549 cells and pneumonia in mice.

Protect the liver and kidney
Scutellarin may be a promising drug for the prevention of liver and renal injury.

Conclusion
Scutellarin is a slightly toxic or non-toxic natural smallmolecule flavone compound with good effects against cardiovascular and cerebrovascular diseases, anti-tumor, anti-insulin resistance, anti-virus, anti-diabetic complications, anti-Alzheimer's disease, liver and renal protection, with a complex mechanism of action involving numerous targets and signaling pathways, and scutellarin exerts these therapeutic effects mainly related to its anti-inflammatory, antioxidant, apoptosis-regulating, and vasodilating effects, but the current study was not specific enough and in-depth enough to explain the link between each target, pathway, and disease as a whole, and was unable to connect them to form a holistic mechanistic network, which requires a more in-depth study [93].In addition, through the collection of animal or cell models in the article, it is found that most experimental results are only preliminary results, and most results lack positive control, which is a lack of reference for the clinical application of candidate drugs.Commonly used drugs, oral and intravenous injections in the formulations based on scutellarin are the mainstream of the current formulation research, among which the injectable products include breviscapine injection, Deng zhan hua Injection, breviscapine sodium chloride injection, breviscapine dextrose injection, the first two of which are more widely used in clinical applications [94].
It has been proved that scutellarin can be used in combination with other drugs to enhance therapeutic efficacy.Therefore, combining scutellarin with other drugs has a promising application prospect.Cocrystallization and nanoformulation technology occupy an important proportion in new drug development, and co-crystallization of scutellarin with other drugs for combination therapy may be a potential way of new drug development.In addition, cocrystallization and nanoformulation can also help to improve the problems of poor stability, poor water solubility, low oral bioavailability, and short in vivo half-life of scutellarin, which has a good prospect for research and development.
As a natural small molecule, scutellarin has good prospects for clinical application and is a potential therapeutic agent for tumors, atherosclerosis, cardiac and cerebral ischemic injuries, diabetic microangiopathy, hyperuricemia, and anti-Alzheimer's disease, etc.However, the current study is not deep enough, and more pharmacological mechanisms of action need to be further explored.Network pharmacology is an interdisciplinary subject between bioinformatics and pharmacology.With the breakthrough of artificial intelligence and other fields, it can better improve the efficiency of research and provide support for the mechanism exploration of candidate natural small molecules.

Fig. 1
Fig. 1 Structure and source of scutellarin

Table 1
Distribution of scutellarin

Table 3
Types of action and models of scutellarin in anti-cardiovascular disease

Table 4
Types of action and models of scutellarin in anti-tumor effect

Table 5
Types of action and models of scutellarin in anti-diabetic effect

Table 6
Types of action and models of scutellarin in Alzheimer's disease

Table 7
Types of action and models of scutellarin in anti-inflammatory and antioxidant effect

Table 8
Types of action and models of scutellarin in other effects